背景:体质错配修复缺陷(CMMRD)综合征是一种罕见且侵袭性的癌症易感综合征。因为这种情况下的数据稀缺导致了管理挑战和糟糕的结果,我们的目的是描述临床谱,癌症生物学,以及遗传学对CMMRD患者生存的影响。
方法:在这项队列研究中,我们收集了所有CMMRD患者的横截面和纵向数据,没有年龄限制,在50多个国家的国际复制修复缺陷联盟(IRRDC)注册。从IRRDC数据库中提取临床数据,医疗记录,和医生填写的病例记录表。主要目的是描述临床特征,癌症谱,和条件的生物学。次要目标包括估计癌症发病率以及特定错配修复基因和基因型对癌症发病和生存的影响。包括癌症监测和免疫疗法干预后。
结果:我们分析了201例患者(103例男性,98名女性)在2007年6月5日至2022年9月9日之间注册。诊断为CMMRD或相关癌症的中位年龄为8·9岁(IQR5·9-12·6),从诊断开始的中位随访时间为7·2年(3·6-14·8)。少数群体和封闭社区中的内亲关系导致血缘关系较低的国家具有较高的纯合性。频繁的皮肤病学表现(完整数据的126例患者中的117[93%])导致与1型神经纤维瘤病的临床重叠(126例中的35[28%])。在201例患者中的194例(97%)中报告了339例癌症。18岁时的累积癌症发病率为90%(95%CI80-99)。患有一种以上癌症的患者的癌症诊断之间的中位时间为1·9年(IQR0·8-3·9)。肿瘤在15个器官中发展,包括早发性成人癌症。中枢神经系统肿瘤是最常见的(173[51%]癌症),其次是胃肠道(75[22%]),血液学(61[18%]),和其他癌症类型(30[9%])。中枢神经系统肿瘤患者的总体生存率最差(在诊断后10年时为39%[95%CI30-52];四种癌症类型的log-rankp<0·0001),其次是血液癌症患者(67%[55-82]),胃肠道癌症(89%[81-97]),和其他实体瘤(96%[88-100])。所有癌症都显示出高突变和微卫星indel负担,和病态突变特征。MLH1或MSH2变体比PMS2或MSH6变体引起更早的癌症发作,生存率较差(PMS2在15岁时的总生存率为63%[95%CI55-73],MSH6为49%[35-68],MLH1为19%[6-66],MSH2为0%;p<0·0001)。与错义变异相比,同一基因内的移码或截短变异导致较早的癌症和较差的结果(p<0·0001)。与PMS2和MSH6变体相比,MLH1和MSH2变体的更大的有害作用持续存在,尽管在监测或免疫检查点抑制剂干预后的存活率总体改善。
结论:CMMRD的非常高的癌症负担和独特的基因组景观突出了综合检测在及时诊断和监测和免疫治疗的精确方法中的益处。这些数据将指导CMMRD存活到成年的儿童和患者的临床管理。
背景:加拿大卫生研究院,站起来对抗癌症儿童肿瘤学组国家癌症研究所社区肿瘤学研究计划,加拿大癌症协会,加拿大大脑,癌症研究V基金会,BioCanRx,Harry和AgnieszkaHall,Meagan\'s步行,加拿大大脑儿童,LivWise基金会,圣包里克基金会,终身持有他们,和Garron家庭癌症中心.
BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD.
METHODS: In this cohort
study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions.
RESULTS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions.
CONCLUSIONS: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD.
BACKGROUND: The Canadian Institutes for Health Research, Stand Up to Cancer, Children\'s Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan\'s Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold\'em for Life, and Garron Family Cancer Center.